Efonidipine hydrochloride which is an active ingredient of a pharmaceutical preparation produced by the present invention is a 1,4-dihydropyridine-5-phosphonic acid derivative of the formula: ##STR2##
and it is a compound which is useful as a medication for circulatory organs having a vasodilative activity and an antihypertensive activity owing to a calcium antagonism.
Efonidipine hydrochloride is a slightly-soluble medication, and has, therefore, a poor absorbability. In order to increase the absorbability, there are a method in which particles of an original medication are subjected to supermicro-particle powdering and a wettability or a dispersibility is improved, and a method in which a solubility of an original medication is improved by formation of a solid dispersion. A method in which a solid dispersion is formed by rendering a medication amorphous attracts special attention. The solid dispersion is a substance obtained by dispersing a medication into a carrier in a monomolecular state. In this dispersion, the medication is retained in a completely amorphous state. In general, an amorphous form is, compared to a crystal form, in a high energy state, and is therefore expected to have a high absorbability.
In a method of producing a solid dispersion of efonidipine hydrochloride, it is known that efonidipine hydrochloride and hydroxypropylmethylcellulose acetate succinate (hereinafter referred to as "HPMC-AS") is dissolved in an organic solvent, and the solvent is removed from the resulting solution through drying under reduced pressure, spray-drying, freeze-drying or the like to form a powdery or particulate product, or the solution is spray-coated on a particulate pharmaceutical excipient as a core through fluidized bed coating, centrifugal fluidized bed coating, pan coating or the like, or the solution is added to a pharmaceutical excipient, and the mixture is kneaded, then dried and formed into a granular product [Japanese Patent Application Laid-open No. Hei 2-49728 (49728/1990), U.S. Pat. No. 4,983,593 and European Patent No. 344,6031].
The method described in these references is excellent as a method of improving a solubility and an absorbability of efonidipine hydrochloride. However, it was problematic in that since a large amount of an organic solvent is used, the production cost is high, and the solvent sometimes remains in the medication.